Abstract In the era of combination antiretroviral therapy (cART) for HIV infection, a major focus of clinical and scientific investigation lies with the high risk of cardiovascular disease, neurocognitive disorders, nephropathy, and malignancy among many other non-AIDS complications. In addition, continuing problems with patient non- compliance and a subsequent resurgence of HIV replication have lead the NIH to prioritize translational HIV research focused on the identification and eradication of viral reservoirs. While strategies are being developed to identify and reverse the latent pool, a parallel effort must proceed to enhance immune defenses against viral persistence as well as re-establish immune homeostasis. The focus of this dual discovery and mechanistic proposal is to identify pathways, molecular targets, and small molecule compounds that regulate immune protection in the HIV patient, whose function is compromised by chronic opioid use and addiction. We hypothesize that an unbiased systems biological evaluation of the T cell, dendritic cell, and B cell transcriptome will reveal specific molecular targets, pathways, or signatures that affect HIV persistence and reservoir size as well as non-AIDS complications. A key corollary of this hypothesis is that chronic opioid addiction, via narcotic pain medication, will perturb these networks and associate with increased HIV persistence, reservoir size, and systemic inflammation. This work will take advantage of two distinct cohorts of virally suppressed HIV+ patients (with and without a prescription-based addiction to the narcotic pain medication Percocet), available in Dr. Avery?s clinic at MetroHealth Medical Center in Cleveland, Ohio, and our already characterized cohort of elite controllers. The work will focus around the following Specific Aims: Aim 1: Identify molecular networks in CD8+ and CD4+ T cell memory subsets, as well as in innate cells, that are differentially regulated in opioid addiction and reciprocally regulated in elite controllers (EC) that naturally control HIV infection. Aim 2: Identify and dissect molecular signatures that are induced by opioid use in memory CD8+ and CD4+ T cells that correlate with inflammation, exhaustion, immune failure, and HIV that are absent in gene expression profiles from elite controllers. Aim 3: Develop and evaluate discrete opioid use specific biomarkers of immune deficiency and comorbidity to inform bioinformatic approaches to identify repurposed drugs to reverse the altered networks. The application of our highly refined transcriptional signature to a Biomarker panel will allow us to rapidly screen a high number of compounds for their ability to rescue opioid-use related immune dysregulation in a very small number of primary cells from cART suppressed HIV+ subjects. Thus, our overall goal is to generate a refined list of therapeutic targets for pharmacologic restoration of immune function in HIV- infected subjects that require opioid therapy for analgesia.